Preparation method of new taxane derivative

A taxane and derivative technology, applied in the field of docetaxel, can solve the problems of unstable intermediates, harsh conditions, many steps, etc., and achieve the effects of overcoming many reaction steps and improving yield

Inactive Publication Date: 2013-08-21
NINGBO INST OF TECH ZHEJIANG UNIV ZHEJIANG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] At present, the route widely adopted for synthesizing docetaxel is to prepare docetaxel by docking with the mother nucleus with the side chain of straight-chain isoserine and the four-membered ring azetidinone, but there are various disadvantages, such as: Many steps, harsh conditions, difficult experimental operation, difficult chiral resolution, high product cost, unstable intermediates, difficult separation, purification and storage of products, etc., are difficult to meet the needs of industrial production

Method used

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  • Preparation method of new taxane derivative
  • Preparation method of new taxane derivative
  • Preparation method of new taxane derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026]

[0027] In a 25 mL round bottom flask, (2R,3S)-3-phenylisoserine methyl ester (1.0 g, 5.1 mmol) was dissolved in toluene, tribromoacetaldehyde (1.57 g, 5.6 mmol) and a catalytic amount of Pyridinium p-toluenesulfonate, oil bath 120 ° C, stirred for 2 hours, TLC detection, raw materials disappeared, stop the reaction, remove toluene under reduced pressure, column chromatography purification (petroleum ether: ethyl acetate = 5: 1) to obtain product 2 : 2.29g, yield 98%.

[0028] (4S,5R)-2-Trichloromethyl-4-phenyl-5-carboxy-1,3-oxazolane: ESI-MS m / z: 455.8454[M+H] + ; 1 H-NMR (400MHz, CDCl 3 ): δ7.52 (d, 2H), 7.51-7.32 (m, 3H), 5.47 (d, 1H), 4.71 (s, 1H), 4.70 (d, 1H), 3.76 (s, 3H).

Embodiment 2

[0030]

[0031]Dissolve compound 2 (457.9mg, 1.0mmol) in 4.5mL ethanol-water (8:1), add lithium hydroxide (71.8mg, 3.0mmol), stir at room temperature for 3h, remove the methanol solvent under reduced pressure, acidify with 2N hydrochloric acid , extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain compound 3: 403.9 mg, yield 91%.

[0032] (4S,5R)-2-Trichloromethyl-4-phenyl-5-carboxy-1,3-oxazolane: ESI-MS m / z: 441.8309[M+H] + ; 1 H-NMR (400MHz, DMSO): δ7.60(d, 2H), 7.36-7.25(m, 3H), 5.42(s, 1H), 5.39(s, 1H), 4.94-4.90(m, 1H), 4.63-4.59 (m, 2H), 4.34 (d, 1H).

Embodiment 3

[0034]

[0035] Dissolve 10-DAB (544.6 mg, 1 mmol) in 5 mL of anhydrous pyridine, under nitrogen protection, under ice-salt bath conditions, slowly add trichloroacetyl chloride (600.0 mg, 3.3 mmol) dropwise, the temperature is controlled at minus 5 degrees, three After the dropwise addition of chloroacetyl chloride was completed, it was naturally raised to room temperature and detected by TLC. After 1.5 hours, the raw material disappeared. Stir and drop in deionized water under ice bath conditions, extract with ethyl acetate, dry with anhydrous sodium sulfate, filter, and reduce pressure The solvent was distilled off, and compound 5 was obtained by column chromatography: 1.08 g, with a yield of 96%.

[0036] 1 H-NMR (400MHz, CDCl 3 ): δ7.67(t, 2H), 7.60(t, 1H), 7.47(t, 2H), 6.27(s, 1H), 5.66-5.60(m, 2H), 4.99(d, 1H), 4.92( d, 1H), 4.60(d, 1H), 4.32(d, 1H), 4.15(d, 1H), 3.98(d, 1H), 2.64-2.62(m, 1H), 2.30(s, 3H), 2.16 (s, 3H), 2.15-1.86(m, 2H), 1.84(s, 3H), 1.14(s, 3H), 1...

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Abstract

The invention discloses a preparation method of new taxane derivative. The method provides an oxazoline side chain produced from reaction of (2R, 3S)-3-phenyl isoserine methyl esters and tribromoacetaldehyde, and then a new taxane derivative is coupled by 10-deacetyl baccatin III whose 7-poistion and 10-position are protected by trichloroacetyl group and oxazoline side chain. The preparation of docetaxel from taxane derivative which is used as an intermediate according to the invention has the advantages of simple synthesis step, few side reactions, high yield, non-isomer by-products, low impurity content, high yield, high purity, greatly reduced cost, and promotion of business preparation of docetaxel. The invention has important meanings in Chinese yew plant species and resource protection and tumour treatment cost reduction, etc., and has great economic benefits.

Description

[0001] This application is a divisional application of the Chinese Invention Patent Application No. (201210033115.1) entitled "An Improved Semi-Synthetic Method for Docetaxel", and the filing date is February 15, 2012. technical field [0002] The present invention relates to an improved semi-synthetic method of docetaxel, in particular to the synthesis of a docetaxel side chain and the modification of the parent ring 10-deacetylbaccatin III (10-DAB), The parent ring is then condensed with the side chain to give docetaxel. Background technique [0003] Paclitaxel (Taxol) is a natural organic compound extracted from the bark or needles of the yew plant. ) crude extracts of paclitaxel were isolated from bark and wood. In the screening experiment, Wani and Wall found that the crude extract of paclitaxel had high activity on mouse tumor cells cultured in vitro, and began to isolate this active ingredient. In 1969, paclitaxel was identified as the active ingredient. Due to the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/12C07D263/04C07D305/14
CPCY02P20/55
Inventor 陈艳君高坤
Owner NINGBO INST OF TECH ZHEJIANG UNIV ZHEJIANG
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